Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history

Abstract

Li-Fraumeni syndrome (LFS) is an autosomal-dominant cancer predisposition disorder associated with pathogenic germline variants in TP53, with a high penetrance over an individual's lifetime. The actual population prevalence of pathogenic germline TP53 mutations is still unclear, most likely due to biased selection of cancer affected families. The aim of this study was to estimate the population prevalence of potentially pathogenic TP53 exonic variants in three sequencing databases, totaling 63,983 unrelated individuals. Potential pathogenicity was defined using an original algorithm combining bioinformatic prediction tools, suggested clinical significance, and functional data. We identified 34 different potentially pathogenic TP53 variants in 131 out of 63,983 individuals (0.2%). Twenty-eight (82%) of these variants fell within the DNA-binding domain of TP53, with an enrichment for specific variants that were not previously identified as LFS mutation hotspots, such as the p.R290H and p.N235S variants. Our findings reveal that the population prevalence of potentially pathogenic TP53 variants may be up to 10 times higher than previously estimated from family-based studies. These results point to the need for further studies aimed at evaluating cancer penetrance modifiers as well as the risk associated between cancer and rare TP53 variants.

Keywords: Li-Fraumeni syndrome; TP53; cancer; genetic variation.

Figure 1 -. Flowchart with a summary of parameters used for variant selection and filtering.

Our analysis is based on a pooled dataset composed by 63,983 individuals, after excluding the TCGA dataset from the ExAC consortium. Variants were annotated using ANNOVAR and selected based on gene region equivalent to exonic and with MAF < 0.01. The canonical transcript NM_00546.5 was used as sequence reference for gene region location based on the RefGene database. Variant classification was established by an original algorithm based on the REVEL score, clinical significance evidences, and the impact on transcriptional activity. Abbreviations: TCGA, The Cancer Genome Atlas; ExAC, Exome Aggregation Consortium; FLOSSIES, Fabulous Ladies Over Seventy; WES, Whole-Exome Sequencing; MAF, Minor Allele Frequency.

Figure 2 -. Distribution of TP53 variants by protein domains.

According to the canonical transcript NM_000546.5, domains of TP53 were divided in: transcriptional activation (residues 1 to 62), proline-rich region (residues 63–97), DNA-binding domain (residues 109–288), oligomerization domain (residues 319–359), and C-terminal regulatory domain (residues 363–393). Point markers do not include duplicate values for variants detected in more than one database. Supp. Table S2 demonstrates exact number of variants in each region.